The WHO clearly identifies tumors as a curable or a chronic disease. The use of natural agents in cancer prevention and therapy is currently playing an important role. Our laboratory has been investigating various natural phenolic compounds, including grifolin, neoalbaconol and epigallocatechin-3-gallate (EGCG). In the present review, we focus on the anticancer activities and the molecular mechanisms of these compounds. Grifolin, a secondary metabolite isolated from the mushroom Albatrellus confluens, has been shown to inhibit cell growth and induce cell cycle arrest in multiple cancer cell lines by targeting extracellular signal-regulated kinase 1 or by upregulating death-associated protein kinase 1 (DAPK1) via p53. We also demonstrated that neoalbaconol, a novel small-molecular compound with a drimane-type sesquiterpenoid structure obtained from Albatrellus confluens, regulates cell metabolism by targeting 3-phosphoinositide-dependent protein kinase 1 (PDK1) and inhibits cancer cell growth. EGCG, a well known catechin found in tea, has gained much attention for its anticancer effects. Previously, we found that it regulates EBV lytic infection through the phosphoinositide-3 kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase (MAPK) pathways in EBV-positive cancer cells. Therefore, these natural agents could be used as potential leading compounds in the prevention of tumor progression and/or EBV-related cancer.